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PXD011926

PXD011926 is an original dataset announced via ProteomeXchange.

Dataset Summary
TitleLztr1 loss leads to Noonan syndrome-like vascular defects by dysregulating vesicular trafficking
DescriptionMutations in LZTR1, an adaptor for cullin 3 (CUL3) ubiquitin ligase complex, are associated with glioma, hepatocarcinoma, paediatric cancers, Schwannomatosis, and Noonan syndrome (NS). NS is a poorly understood and complex disease. The variety of NS phenotypes makes it challenging to elucidate the molecular mechanisms by which mutations in LZTR1 drive human disease. Using an Lztr1 knockout model, we assessed the effect of Lztr1 loss on endothelial function. Moreover, the molecular alterations mediated by Lztr1 loss were evaluated by mass-spectrometry (MS)-based ubiquitome and proteome analysis. These analyses demonstrated that Lztr1 loss affects vesicular trafficking. We identified the ESCRT III member CHMP1B as a substrate for the LZTR1/CUL3 ubiquitin complex and could show that disease-related LZTR1 mutations abolish the interaction with CHMP1B. LZTR1-mediated ubiquitination of CHMP1B facilitates its interaction with IST1 that affects the dynamics of fusion and fission of endosomal vesicles. Dysregulation of vesicular trafficking triggered by Lztr1 loss leads to up-regulation of VEGF signaling due to endosomal accumulation and activation of VEGFR2. This novel molecular mechanism provides a fundamental explanation for the role of LZTR1 in endothelial function and justify the use of anti-VEGF therapies for the treatment of NS patients.
HostingRepositoryPRIDE
AnnounceDate2024-10-22
AnnouncementXMLSubmission_2024-10-22_05:13:26.275.xml
DigitalObjectIdentifier
ReviewLevelPeer-reviewed dataset
DatasetOriginOriginal dataset
RepositorySupportUnsupported dataset by repository
PrimarySubmitterImpens Francis
SpeciesList scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationListubiquitinylated lysine; monohydroxylated residue; acetylated residue; iodoacetamide derivatized residue
InstrumentQ Exactive HF; LTQ Orbitrap Elite
Dataset History
RevisionDatetimeStatusChangeLog Entry
02018-12-03 08:27:16ID requested
12020-10-13 22:59:52announced
22024-10-22 05:13:27announced2024-10-22: Updated project metadata.
Publication List
10.1161/circresaha.119.315730;
Sewduth RN, Pandolfi S, Steklov M, Sheryazdanova A, Zhao P, Criem N, Baietti MF, Lechat B, Quarck R, Impens F, Sablina AA, Controls Cardiovascular Function by Regulating Vesicular Trafficking. Circ Res, 126(10):1379-1393(2020) [pubmed]
Keyword List
curator keyword: Biomedical
submitter keyword: HeLa cells, VEGF,Noonan syndrome, Lztr1, vesicular trafficking, ubiquitin, CHMP1B
Contact List
Anna A Sablina
contact affiliationVIB-KU Leuven Center for Cancer Biology, VIB, Leuven, Belgium Department of Oncology, KU Leuven, Herestraat 49, Leuven, Belgium
contact emailanna.sablina@kuleuven.vib.be
lab head
Impens Francis
contact affiliationVIB Proteomics Core Ghent University
contact emailfrancis.impens@vib-ugent.be
dataset submitter
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